Discrimination is a social construct that discredits individuals based on attributes deemed socially undesirable. Adolescence is a period of transition where individuals acquire skills, values, and experiences that prepare them for adulthood. Adverse experiences during adolescence could particularly affect these acquisitions. For adolescents, discrimination is an experience that can lead to social and health consequences. Our hypothesis is that adolescents with chronic disease are more likely to be exposed to discrimination than their healthy peers. This systematic review aimed to study the prevalence, nature, and the additional risk of discrimination in adolescents with chronic disease compared to their healthy peers. A systematic review was conducted following PRISMA guidelines, including both quantitative and qualitative studies, published between January 2000 and December 2022. Searches were conducted using several electronic databases, including PubMed, COCHRANE, PsycINFO, EMBASE, CAIRN, and CINAHL. Included articles studied adolescents between 12 and 18 years old affected by one of the most prevalent chronic diseases (obesity, epilepsy, diabetes, respiratory diseases including asthma and cystic fibrosis, cancer, and cardiovascular disease). Those articles reported discrimination from the adolescents' perspective and studied the association between discrimination and disease. We identified 27 studies conducted across almost all continents, including a total of 3,290,446 adolescents. Most of the studies are cross-sectional and recent (published after 2017). They are mainly focused on obesity and epilepsy. All types of discrimination were studied, although cyberbullying was explored in only one study. The prevalence of discrimination was reported in 11 studies and varies depending on the type of chronic disease and contexts (from 14% in adolescents with cystic fibrosis to 99% in adolescents with diabetes). Discrimination was mostly self-reported by the adolescents and it came from multiple sources: peers, parents, or educational and healthcare professionals. It seems that the presence of a chronic disease exposes individuals to an additional risk of discrimination, even though quantifying this risk was not possible due to the diversity of methods. Conclusion: Discrimination against adolescents with chronic diseases has received poorly studied in literature even though they appear to be more vulnerable than their peers. The phenomenon is complex since discrimination occurs through several forms and originates from diverse sources. Given the multiple repercussions of discrimination on all aspects of adolescents' life and development, it is essential to study it further. Awareness of discrimination's diversity will allow to establish preventing actions. Early screening could help limit discrimination's prejudice on adolescents' quality of life. What is Known: Discrimination has a significant impact on the life of individuals who experienced it.• Some risk factors of discrimination are already known, e.g., age, gender, disability, ethnic origin. There is no strong evidence that having a chronic disease at adolescence increases the risk of discrimination. What is New: Adolescents with chronic disease have an additional risk of discrimination coming from their peers, their parents, and professionals. • The discrimination could be explained by the permanent physical difference, the occasional visibility of the symptoms or physical limitations, and the sociocultural constructs of the disease.